Baseline Immunoglobulin E Levels as a Marker of Doxorubicin- and Trastuzumab-Associated Cardiac Dysfunction

Abstract

Rationale There is a critical need to develop robust, mechanistic strategies to identify patients at increased risk of cancer therapeutics-related cardiac dysfunction (CTRCD). Objective We aimed to discover new biomarkers associated with doxorubicin and trastuzumab-induced CTRCD using high-throughput proteomic profiling. Methods and Results Plasma, echocardiograms, and clinical outcomes were collected at standardized intervals in breast cancer patients undergoing doxorubicin and trastuzumab cancer therapy. Thirty-one longitudinal plasma samples from three cases with CTRCD and four age- and cancer-matched controls without CTRCD were processed and analyzed using label-free liquid chromatography- mass spectrometry (LC-MS). From these analyses, 862 proteins were identified from case/control pairs 1 and 2, and 1,360 proteins from case/control pair 3. Proteins with a greater than 1.5-fold change in cases compared to controls with a p<0.05 either at the time of CTRCD diagnosis or across all timepoints were considered candidate diagnostic or predictive biomarkers, respectively. The protein that demonstrated the largest differences between cases and controls was immunoglobulin E (IgE), with higher levels detected at baseline and across all timepoints in controls without CTRCD as compared to matched CTRCD cases (p<0.05). Similarly, in a validation study of 35 participants treated with doxorubicin and trastuzumab, high baseline IgE levels were associated with a significantly lower risk of CTRCD (p=0.018). Conclusions In patients receiving doxorubicin and trastuzumab, high baseline IgE levels are associated with a lower risk of CTRCD. These novel findings suggest a new paradigm in cardio-oncology, implicating the immune system as a potential mediator of doxorubicin and trastuzumab-induced cardiac dysfunction.

Precision Cardio-Oncology

“…The importance of energy metabolism was also confirmed in daunorubicin-induced cardiotoxicity, with alterations in mitochondrial proteins involved in oxidative phosphorylation and energy channeling along with increased proteins involved in autophagy, membrane repair, and apoptosis (20). Small human studies have also suggested the importance of the immune system in the pathophysiology of cardiotoxicity (21). Nevertheless, findings from proteomic studies are still largely preliminary.…”

Mass Spectrometry‐Based Analysis of Time‐Resolved Proteome Quantification

“…In both studies, an increase of the protein serum amyloid A was observed. In the case of cardiovascular biomarkers, the timespan varies from minutes when studying novel candidates for early myocardial injury, to hours or months when studying markers of cardiac dysfunction. In this last study, among the 1000 proteins identified in different case/control patients, immunoglobulin E was the protein with the largest differences between cases and controls.…”

Cardiac Dysfunction Due to Cancer Therapy

“…Beer et al, 3 in this issue of Circulation Research, have taken an alternative agnostic approach to identify biomarkers that might be used to evaluate risk for chemotherapy-associated cardiac injury and heart failure. Serial plasma samples were collected from a carefully characterized group of breast cancer patients treated with anthracycline and trastuzumab.…”